Chronic hepatitis C virus (HCV) infection is often associated with extrahepatic manifestations, including central nervous system (CNS) damage and neuropsychiatric impairments that can be exacerbated by alcohol abuse. More than half of patients with chronic HCV infection complain of ?brain fog? (impaired cognition, fatigue). The introduction of direct-acting antiviral (DAA) therapies has revolutionized HCV treatment, with sustained viral response (SVR) rates of ~90%. The VA is now offering DAA therapy to all Veterans with HCV treated within VA health care systems, including those with alcohol use disorders (AUDs)?a common co-morbidity among Veterans with HCV. Despite this progress and expansion in HCV treatment efforts, there are insufficient data on brain function outcomes (e.g., outcomes that affect daily life such as cognitive abilities, fatigue, and substance abuse behavior) following DAA therapy. There are also limited data on the effects of viral clearance on inflammatory factors that putatively influence neuropsychiatric function. This Merit Review project plans to conduct a longitudinal study of adults (with and without AUDs) undergoing antiviral therapy for the treatment of HCV. Demographically- matched comparison groups of Veterans without HCV (with and without AUD) will also be evaluated to determine the relative contribution of HCV to outcomes that are affected by alcohol abuse. It is hypothesized that adults with HCV and co-morbid AUDs may be at increased risk of persistent brain dysfunction following DAA therapy. By comparing neuropsychiatric functioning, cortical activity, white matter integrity, and immune response among Veterans with and without active AUD before and after DAA therapy, results from this study are expected to determine the extent of improvement in brain function (e.g., neural connectivity and cognitive abilities) and reduction in inflammation that is achieved by successful completion of DAA therapy. Two specific aims are proposed. Aim 1 will evaluate the impact of DAA therapy on CNS function in Veterans with HCV and will test the hypotheses that following DAA therapy and obtaining an SVR, participants will show: i) improved neuropsychiatric outcomes (e.g., cognitive function, fatigue, mood), as compared to baseline (pre-DAA therapy), ii) restored functional connectivity and disintegrity within white matter tracks that had detectable deficits at baseline, and iii) normalization of immune activation profiles (e.g., decreased expression of inflammatory cytokines and restored T cell phenotypes), as compared to baseline. Aim 2 will use general linear models to assess whether change in the response (e.g., CNS functional outcomes) between post- and pre-DAA therapy differs among the four groups?either due to AUD, HCV, or the potential interaction of these factors?to determine the impact of an active AUD on neuropsychiatric, neuroimaging, and immunological outcomes. Participants will be assessed at baseline and 12 weeks post-therapy. Evaluations will incorporate brain imaging methods [i.e., resting state magnetic resonance imaging (MRI), functional MRI, and diffusion tensor imaging] along with clinical and laboratory methods to determine the interactive effects of alcohol use and obtaining an SVR on brain function and inflammatory processes. Clinical and laboratory data will include: i) demographic and medical information, ii) neuropsychological measures of attention, memory, and executive function, iii) neuropsychiatric symptom questionnaires (e.g., depression, fatigue), iv) urine and oral fluid collection for medical laboratory tests, and v) blood sample collection for flow cytometry, qPCR, and multiplex immunoassays to measure key immune factors, such as interleukin (IL) -1?, IL-8, IL-10, S100B, and C-reactive protein and for contribution to the VA Liver Disease Repository. Collectively, the results from this project seek to identify biomarkers of brain recovery and inform targeted treatment strategies that will maximize the long-term clinical benefits of HCV antiviral therapy.